Malaria still afflicts about half of the world populations causing more than 500,000 deaths, mostly children. The global economic toll of malaria is enormous. Most of the drugs that are currently utilized for malaria treatment are losing their effectiveness due to widespread emergence of drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line therapies against falciparum malaria are showing signs of resistance in endemic regions. Therefore, it is urgent to identify new drug leads acting on novel targets for the development of next generation of therapies against malaria. To address the fragility of malaria therapy, we propose to identify novel lead compounds against multidrug resistant malaria through screening of a library of fungal secondary metabolites. We believe that fungal secondary metabolites, which are underexplored for antimalarial discovery, provides us with a unique opportunity to investigate medicinally relevant but untapped chemical space for the discovery of novel malaria therapeutics. Our preliminary screen has identified fungal extracts and pure compounds from fungal extracts with potent antiplasmodial activities. Based on our promising preliminary results we hypothesize that fungal extracts will be a rich source of novel antimalarial scaffolds. To prove this hypothesis, we propose herein to discover antimalarial lead compounds from fungal secondary metabolites effective against multidrug resistant malaria. The research in this endeavor will be conducted through a multidisciplinary collaboration between the laboratories of Debopam Chakrabarti (University of Central Florida) and Robert Cichewicz (University of Oklahoma), with combined expertise in natural product chemistry, malaria cell biology, and anti- infective discovery. Specifically, (1) We will screen libraries of 5,000 extracts derived from diverse fungal species and 800 pure compounds of fungal origin to identify selective antiplasmodial activities against both asexual and gametocyte stages; hits will be screened against multidrug resistant strains to determine cross-resistance, and (2) We will initiate dereplication of prioritized bioactive secondary metabolites and determine the structures of active compounds. (3) Active compounds will be prioritized by in vitro pharmacology, gametocytocidal activities, and stage specific action for future in vivo studies.This is a highly significant endeavor, as we will discover novel lead compounds for therapy against multidrug resistant malaria.